Aerosols are increasingly being used for delivering medication for therapeutic treatment of the lungs. For example, in the treatment of asthma, inhalers are commonly used for delivering bronchodilators such as β2 agonists and anti-inflammatory agents such as corticosteroids. Two types of inhalers are common use, metered dose inhalers (MDIs) and dry powder inhalers (DPIs). Both types have as their object the delivery of medication, which is typically in the form of a solid particulate or powder, into the airways of the lungs at the location of the condition being treated.
In the MDI device, the medication is provided by the pharmaceutical manufacturer in a pressurized aerosol canister, with the medication being suspended or dissolved in a liquid propellant such as a hydrofluoroalkane (IIFA) or chlorofluorocarbon (CFC). The canister includes a metering valve having a hollow discharge stem which can be depressed inward into the canister to discharge a metered volume of propellant-medication mixture in the form of an aerosol comprising fine droplets of propellant in which particles of the medication are suspended or dissolved. A typical MDI for use with such a canister includes a housing having an actuator and nozzle. The canister is inserted into the housing with the hollow discharge stem of the canister being received in a bore in the actuator. Depressing the closed end of the canister causes the stem to be pushed inward into the canister so that a metered volume of drug-containing propellant formulation is discharged through the nozzle resulting in an aerosol plume comprised of drug-containing propellant droplets or drug particles (the Aerosol Bolus). The housing further defines a flow path in fluid communication with the nozzle, the flow path in having an outlet at a mouthpiece portion of the housing, such that the aerosolized medication may be inhaled after it exits the mouthpiece portion. The patient either inserts the mouthpiece into the mouth with the lips closed around the mouthpiece, or holds the mouthpiece at a slight distance away from an open mouth. The patient then depresses the canister to discharge the medication, and simultaneously inhales the Aerosol Bolus.
As used herein, the terms plume, medicament plume, discharge plume and similar terms are synonymous with Aerosol Bolus.
Several current versions of the pMDI include automatic actuators in which the breathing through the device causes the discharge of an Aerosol Bolus. These are termed Breath Actuated pMDIs or BApMDIs.
Most pMDIs have poor delivery efficiency—the ratio of drug delivered to the lungs divided by the nominal or metered dose. Typically pMDIs deliver less than 20 percent of the metered or nominal dose to the targeted biospace. Poor delivery efficiency is caused by a number of factors. One of these is incomplete evaporation of propellant in the Aerosol Bolus, resulting in a large portion of the metered dose being delivered in large droplets or particles which cannot be inhaled into the lungs. For effective delivery of the Aerosol Bolus to the conductive airways (bronchi, and subbronchioli) and the deep lungs (alveolar region), it is desirable that most of the drug-containing aerosol particles or droplets should have velocities matching that of the inspired breath at the mouth—preferably less than 300 centimeters per second to avoid impaction in oropharyngeal cavity, and less than 150 centimeters per second to avoid impation in the trachea and bronchi. Additionally the aerosol droplets or particles which are inspired, should be less than about 10 microns (10−5 meters) mass median aerodynamic diameter (MMAD) in size to avoid deposition in the oropharyngeal cavity, and preferably should be between about 1 micron and 5 microns MMAD to deposit in the lungs and conductive airways. Incomplete evaporation of propellant at the outlet of the mouthpiece results in a substantial fraction of the metered dose being delivered in the form of relatively large drug-containing propellant droplets with the majority having MMADs greater than 10 microns.
Another factor contributing to poor efficiency is high linear velocity and trajectory of the aerosol plume as it exits the mouthpiece. Ideally, the velocity of the aerosol should match the velocity of the patient's inspired breath so that the particles are entrained in the breath and carried into the lungs. But with most commercial pMDIs, the exit velocity of the aerosol substantially exceeds the velocity of the patient's breath. Most discharge the aerosol plume at high velocity, often exceeding 2000 centimeters/second, in a straight line trajectory, at a distance less than 10 centimeters from the back of the throat. Such droplets cannot be entrained in the patient's breath and efficiently inspired because their momentum—the product of their mass and velocity—is too high. A factor contributing to the poor delivery efficiency of most existing MDIs is excessive length of the plume or bolus of aerosol exiting the device. In most existing MDIs, this length typically exceeds 25 centimeters, and the aerosol plume is discharged typically less than 10 centimeters from the back of the throat which makes it difficult for the patient to inhale the entire bolus.
The large, high velocity aerosol droplets or particles generated by most pMDIs tend to impact the inside of the mouth and at the back of the patient's throat, with the result that much of the medication is swallowed and only a small fraction is delivered beyond the oropharyngeal cavity. The local concentration of medication in the mouth and throat can cause local side effects such as immunosuppression resulting in infections such as thrush development of fungal infections in the case of corticosteroids. Additionally, swallowing the drugs can lead to systemic absorption resulting in undesired systemic side effects. For example 32 agonists, a common medicament delivered by MDI's cause undesired heart rate increases, blood pressure elevation, muscle tremors, restlessness and insomnia when absorbed systemically via gastrointestinal absorption. Further the wasted medication has been estimated to cost U.S. patients about $750 million per year.
In an effort to decrease plume velocity, some MDI designers have added tubular high volume spacers between the inhaler mouthpiece and the patient's mouth. Examples include spacers from Trudell, Astra and others. Although spacers improve delivery efficiency, most of the dug which is discharged from the inhaler impacts and sticks on inner surfaces of the spacer, and is therefore unavailable for inhalation by the user. Thus, MDIs with spacers still suffer from unacceptably low delivery efficiencies.
Accordingly, it has been an object of the present invention to provide a method and inhaler apparatus for delivering an aerosolized medication in which the respirable fraction of the metered dose i.e., the fraction in the form of particles or droplets (Aerosol Bolus) that are respirable, having at a minimum, an MMAD of less than 10 microns, and preferably an MMAD between about 1 and about 5 microns at the exit of the inhaler apparatus.
It has been a further object of the present invention to provide a method and apparatus for delivering an aerosolized medication in which the linear velocity of the Aerosol Bolus at the exit of the apparatus approximately matches the velocity of the patient's inspired breath.
It has been another object of the invention to maximize dispersion and mixing of the drug-containing aerosol particles or droplets (Aerosol Bolus) in the inspiratory breath within an inhaler apparatus.
It has been a still further object of the present invention to provide a method and apparatus for delivering an aerosolized medication in which the length of the bolus of aerosolized medication which exits the apparatus is as short as possible and in which the Aerosol Bolus has a nonlinear trajectory.
A further object of the invention has been to provide a method and apparatus for maximizing the evaporation of liquid propellant in an inhaler.
Still another object of the invention has been to provide a method and apparatus for delivering an aerosolized medication in which impaction and sticking of medication on the inner walls of the apparatus is minimized by providing multiple vortex elements along the entire path of the plume from where it exits the discharge stem of the metering valve to where it exits the mouthpiece.